Anthracyclines are among the most active antitumor agents. They are important in the treatment of leukemia and solid tumors. Among anthracyclines, adriamycin (doxorubicin) (1) is a broad spectrum antitumor drug of significant clinical utility. Arcamone, F. (1981) Doxorubicin Anticancer Antibiotics, Academic Press, New York. Daunomycin (daunorubucin) (2) is also used widely to treat leukemia. Menogaril (3), a semisynthetic anthracycline, whose structure is quite different from (1) and (2), is an antitumor drug in phase II of clinical trials. Vance, R. B. et al. (1991) Investigation New Drugs 9:73. ##STR1##
Anthracyclines are believed to exert their antitumor activity and their cytotoxicity because they are able to intercalate in and cleave DNA, and/or catalysis of superoxide formation, and/or they can be bioreduced to the corresponding quinone methides (Q.M., e.g., 4) that can function as alkylating agents, and catalysts for oxygen reduction, leading to highly toxic radicals. Tewey, KM et al. Science (1984) 226:466; Bachur, NR et al. Proc. Natl. Acad. Sci. USA (1979) 76:954; Gaudiano, G; Koch, T, Chem. Res. in Toxicology (1991) 4:2; Moore, HW, Czerniak, R Med. Res. Rev. (1981) 1:249; Lin, T-S et al. J. Med. Chem. (1984) 111:2283; Abdella, BRJ, Fisher, J Environ. Health Perspect. (1985) 64:3; Thompson, DC et al. Chem.-Biol. Interact. (1992) 86:129. The intercalation process appears to be augmented through anthracycline interaction with the cell membrane. Tritton, T, Pharmacol. Ther. (1991) 49:293. The formation of superoxide is thought to result in oxidative stress which in the myocardium is a possible source of cardiotoxicity. Myers, CE et al. Science (1977) 197:165; Doroshow, JH et al. J. Biol. Chem (1986) 261:3068.
Multidrug resistance can be induced upon administration of anthracyclines, particularly adriamycin. Multidrug resistance is characterized by resistance to several drugs developed by a variety of tumor cells upon treatment with adriamycin or other single drugs. Mechanisms proposed for tumor cell multidrug resistance include over expression of P-170-glycoprotein or other proteins, resulting in enhanced efflux of the drug and increased glutathione concentration and over expression of glutathione transferase. Volm, M et al. Br. J. Cancer (1991) 64:700; Giai, M et al. Eur. J. Gynecol. Oncol. (1991) 12:359; Black SM, Wolf, CR Pharmacol. Ther. (1991) 51:139.
Glutathione transferase catalyzes the formation of drug-glutathione conjugates which commonly, but not always, have lower cytotoxicity and/or may be expelled from the cell. Anders, MW et al. Xenobiotics (1992) 22:1135; Olson, JA et al. J. Nutr. (1992) 122(3rd Suppl.):615; Waxman, DJ Cancer Res. (1990) 50: 6449; Baillie, TA et al. Acc. Chem. Res. (1991) 24:264; Tsuchida, S. et al. Rev. Biochem. Mol. Biol. (1992) 27:337; Schecter, RL et al. Biochem Cell Biol. (1992) 70:439. A significant increase in glutathione concentration and glutathione transferase activity has been reported in adriamycin insensitive cells relative to sensitive cells. Meijer, C et al. Int. J. Cancer (1991) 49:582; Peters, WH, Roelofs, HMJ Cancer Res. (1992) 52:1886.
The synthesis of a number of anthracyclines carrying a variety of different substituents at the position C-7 has been reported. Some of these derivatives have been used as antitumor drugs. It is also known that in the anthracyclines used as antitumorals, the residue at position C-7 is usually polar in nature. No successful synthesis of anthracycline derivatives with C-7 peptide residues has been reported. Houee-Levin, C. et al. (1991) Free Rad. in Biol. Med. 11:573) reported a failed attempt to synthesize the glutathione derivative of daunomycin.